This patent application claims a benefit of priority from Korean Patent Application No. 2000/11563 filled Mar. 8, 2000 through PCT application Ser. No. PCT/KR01/00358 filed Mar.8, 2001, the contents of each of which are incorporated herein by reference.
The present invention relates to a novel 7,8-dihydro-xanthenone-8-carboxylic acid derivative, the preparation thereof, and pharmaceutical compositions comprising the 7,8-dihydro-xanthenone-8-carboxylic acid derivative as a pharmaceutically active ingredient. More particularly, the present invention relates to a 7,8-dihydro-xanthenone-8-carboxylic acid derivative, which inhibits angiogenesis and tumor growth, a method for preparing such a compound from fungi, and pharmaceutical compositions comprising such a compound as a pharmaceutically active ingredient, which are effective for the treatment of angiogenic diseases, such as cancers, rheumatoid arthritis and diabetic retinopathy.
Cancer, one of the most intractable diseases, has been extensively studied to develop anti-cancer agents. The most of anti-cancer agents developed thus far are, however, low specific for cancer cells, so as to cause serious side effects. Further, owing to their heterogeneity and genetic instability, cancer cells acquire resistance to the anti-cancer agents. Taking advantage of recent advances in our understanding of angiogenesis in tumors, research all over the world has been directed toward the development of anti-angiogenic agents to solve the conventional problems of anti-cancer agents.
Angiogenesis is a complex process in which capillary blood vessels grow in a complex physiological processes (J. Folkman and M. Klagsbrun, Science, 235, 442-447, 1987); J. Folkman and Y. Shing, J. Biol. Chem., 267, 10931-10934, 1992). Angiogenesis is driven by a complex array of soluble mediators, matrix molecules and accessory cells that function to fine-tune and coordinate the response in both time and space. The initiation of angiogenesis is mediated by multiple molecules that are released from a number of sources including inflammatory cells, such as mast cells and macrophage as well as a variety of tumor cells. These molecules activate the normally quiescent vascular endothelium by binding to their respective receptors. These activated endothelial cells have a characteristic set of traits which include increased cellular proliferation, elevated expression of cell adhesion molecules, increased secretion of proteolytic enzymes, increased cellular migration and invasion, and differentiation to capillary tube. These complex cellular processes should be successfully accomplished to complete angiogenesis.
The relation between cancer and angiogenesis has been studied since Dr. Judah Folkman has hypothesized in 1971 that angiogenesis might be indispensable for the growth of tumors (J. Folkman, New England Journal of Medicine, 285, 1182-1186, 1971). Solid tumors can not grow beyond the size of 1-2 mm without inducing the formation of new blood vessels to supply needs of the tumor such as growth factors, oxygen and nutrients. Accordingly, blocking the angiogenesis around tumors can inhibit the growth and metastasis of tumors. In 1990, it was also found that fumagillin, a naturally occurring compound, inhibits angiogenesis (D. Ingber, T. Fujita, et al., Nature, 348, 555-557, 1990). Since then, much attention has been paid to the development of novel angiogenesis inhibitors. For instance, angiostatin (M. S. O""Reilly et al., Cell, 79, 315-328, 1994) and endostatin (M. S. O""Reilly et al., Cell, 88, 277-285, 1997), both endogenous angiogenesis inhibitors, have recently been proven to have potent anti-cancer activity in animal tests, attracting more attention to angiogenesis inhibitors as anti-cancer agents.
Angiogenesis inhibitors have many advantages over conventional anti-cancer agents as following. Firstly, angiogenesis inhibitors can prevent the growth and metastasis of cancer cells simultaneously because angiogenesis is indispensable for the growth and metastasis of tumors. Secondly, the mutation of cancer cells into drug resistant phenotypes, which usually occurs owing to the heterogeneity and genetic instability of cancer cells, is not caused by angiogenesis inhibitors because they target not cancer cells, which are aneuploids, but normal endothelial cells, which are diploids. Thirdly, angiogenesis inhibitors are effective over all cancer species that absolutely require angiogenesis while conventional anti-cancer agents are effective against only limited cancer species. Lastly, because angiogenesis rarely occurs in normal adults except in special instances, for instance, wound healing and female menstruation, angiogenesis inhibitors would greatly reduce side effects, which are usual for conventional anti-cancer agents.
In addition, angiogenesis inhibitors are expected to be therapeutically effective against angiogenic diseases, such as rheumatoid arthritis, diabetic retinopathy, etc.
In the screening of angiogenesis inhibitors, inventors have found that a novel fungal strain isolated from soil produces 7,8-dihydro-xanthenone-8-carboxylic acid derivative, which inhibits angiogenesis as well as tumor growth.
Therefore, the present invention provides a novel 7,8-dihydro-xanthenone-8-carboxylic acid derivative represented by the chemical formula 1. 
The present invention provides a novel microorganism, Aspergillus sp. Y80118 (Accession No: KCTC 0737BP).
The present invention also provides a method for preparing a 7,8-dihydro-xanthenone-8-carboxylic acid derivative from Aspergillus sp. Y80118 (Accession No: KCTC 0737BP).
The present invention also provides a use of 7,8-dihydro-xanthenone-8-carboxylic acid derivative as an inhibitor of VEGF (vascular endothelial growth factor) function or angiogenesis.
The present invention further provides pharmaceutical compositions comprising the 7,8-dihydro-xanthenone-8-carboxylic acid derivative as a pharmaceutically active ingredient for the treatment of angiogenic diseases.